Biology subjects

Joshi, P. A.

Publications and source records attributed to Joshi, P. A..

4 recordsLinked to original sources

bioRxiv2025

A sex hormone-BDNF-TrkB axis directs sympathetic innervation in the mouse mammary gland

Stromal-epithelial interactions underlie fundamental tissue morphogenesis in normal development, tissue regeneration and cancer. Peripheral nerves are increasingly implicated as important stromal drivers of normal and malignant epithelial tissue biology. In the mammary gland, epithelial cell fate is highly dependent on stromal cues during distinct stages of postnatal growth which are triggered by ovarian sex hormones estrogen and progesterone. However, the effects of sex hormones on peripheral nerves in the postnatal mammary gland is largely unknown. Here, we uncover extensive changes in peripheral sympathetic innervation in the mammary stromal microenvironment during puberty and pregnancy which are periods of active postnatal mammary epithelial growth. We find that sex hormones induce sympathetic axonal branching through an intricate hormone-epithelial-nerve cross-talk. Specifically, estrogen and progesterone stimulate the expression of brain-derived neurotrophic factor (BDNF) in mammary hormone receptor- expressing luminal epithelial cells which acts on Tropomyosin receptor kinase B (TrkB)- expressing sympathetic nerves to activate BDNF-TrkB signaling. Our findings illustrate a previously unrecognized capacity of hormone-sensing epithelial cells to modulate sympathetic innervation, providing a framework for understanding nerve dynamics during tissue regeneration and cancer.

molecular biology↗

bioRxiv2024

PDGFRα+ Mesenchymal Stromal Cells Contribute to Epithelial Lineages during Prostate Development

Organ development is attributed to stem/progenitor cells which self-renew and differentiate into mature cells critical for tissue form and function. The prostate is an epithelial organ that participates in the production of seminal fluid. Bipotent and unipotent stem/progenitor cells resident in prostatic epithelia are shown to support its development. While the stroma is crucial for prostate organogenesis, precise stromal cells including immature stromal subsets involved in prostate biology are unknown. Utilizing genetic reporter and lineage tracing mouse models, we identify a PDGFR+ mesenchymal population in the fibromuscular stroma that harbors progenitors which undergo a mesenchymal-to-epithelial transition, generating prostatic luminal and basal epithelial lineages during postnatal development. Further, these mesenchymal progenitors and their epithelial progeny persist in the adult, demonstrating their self-renewal potential. Our findings unveil a prostatic progenitor beyond the epithelium, laying down a framework for probing the contribution of stromal progenitors to the normal and diseased prostate. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/626405v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@807278org.highwire.dtl.DTLVardef@db4350org.highwire.dtl.DTLVardef@12043e2org.highwire.dtl.DTLVardef@148cee9_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Adipocyte progenitors are primary contributors to the disrupted epithelial niche that is sustained following abrupt mammary gland involution

A short duration of breastfeeding is a risk factor for the development of high-mortality, postpartum, triple-negative breast cancer. The intrinsic properties of cancer-initiating epithelial cells that persist following breastfeeding cessation and mammary gland remodeling are poorly understood. Previously, we showed that Platelet-Derived Growth Factor Receptor alpha (PDGFR)-expressing stromal mammary adipocyte progenitors (MAPs) differentiate into epithelial luminal progenitors in the adult gland. In the current study, we demonstrate that MAP-derived luminal progenitors retain a mesenchymal transcriptomic signature. In an abrupt involution model that mimics a short breastfeeding duration, MAP-derived luminal progenitors persist and dominate luminal epithelia, undergoing transcriptomic alterations that signify a distinct ferrometabolic state linked to cancer. Concurrently, MAPs adopt an alternative interferon-mediated profibrotic and invasive stromal fate. Our work uncovers MAPs to be the primary cellular origin of a pathological stromal and epithelial microenvironment following abrupt involution, presenting a potential therapeutic target in postpartum breast cancer.

cancer biology↗

bioRxiv2023

Obesity modifies cell fate plasticity of Pdgfrα-expressing mammary adipocyte progenitors to promote an aberrant mammary microenvironment

Excess fat gain culminating in obesity is a mounting global pandemic associated with a myriad of diseases including a higher risk of developing multiple cancers such as breast cancer. The underlying biological basis for obesity-linked breast cancer is attributed to alterations in adipose tissue-derived endocrine, metabolic and inflammatory factors. However, the precise cell types responsible for generating a cancer-susceptible mammary gland in obesity are not well understood. Using diet-induced obesity in conjunction with genetic reporter mouse models, we reveal elevated mammary adipocyte progenitors (MAPs) expressing Platelet-Derived Growth Factor Receptor alpha (PDGFR) in the mammary tissue microenvironment during obesity. Single-cell RNA sequencing analysis demonstrate intensified obesity-driven trajectories of MAPs to immune and epithelial progenitor cells. Further, lineage tracing indicates an invasive cellular state of MAPs that confers greater access of MAP descendants into the mammary epithelium concomitant with their transition into immune and epithelial cell fates. MAPs in obesity exhibit heightened activation of cancer-associated and inflammatory pathways where Egfr is identified as a common target upregulated in MAPs. Mechanistic studies on purified MAPs with a major obesity diet component and EGFR stimulation corroborate dynamic EGFR-mediated MAP responses. Our findings uncover MAPs as key contributors to forging an aberrant mammary gland in obesity, providing insight into the potential utility of targeting this cell lineage for eradicating cancer risk related to augmented adiposity.

cell biology↗